Baran Group Meeting I.S. Young So Many Hof(f)man(n)s 5/10/2008 Hof(f)man(n)s Discussed Hof(f)man(n) #2 (Many contributions to chemistry) - K. A. Hofmann and J. Sand (Paper from 1900, no other info available) - studied under Justus von Liebig (University of - oxymercuration of alkenes Giessen) - taught in Bonn, London and Berlin August Wilhelm von Hofmann (1818-1892) - many named reaction and aniline dyes - first to use molecular models (colors still conserved) Felix Hoffmann (1868-1946) - invented many named reactions - first useful synthesis of aspirin and heroin August Wilhelm Albert Hofmann (1906-2008) von Hofmann - his student (Perkin) responsible for aniline dyes - father of LSD and first synthesis of psilocybin Roald Hoffmann (Cornell University) Hofmann Rearrangement (Ber. 1881, 14, 2725.) - organic and inorganic chemist, 1981 Nobel Prize (orbital symmetry) O For base sensitive substrates Br2 O H2O C can use hypervalent iodine or Robert V. Hoffman (Professor Emeritus, New Mexico State University) R R-NH2 R NH2 NaOH N -CO lead tetraacetate - chemistry of N-sulfonyloxy compounds 2 Example from Recent Literature (J. Am. Chem. Soc. 1998, 120, 8259) Reinhard W. Hoffmann (Professor at University of Marburg, Germany) - natural product synthesis and reactive organometallic compounds OMe OMe OMe PMPO MOMO PMPO MOMO HO H. Martin R. Hoffmann (Professor at Hannover University, Germany) O Br2 O NaOMe - chiral allyl cations, chemistry of cinchona alkaloids, natural product Steps O synthesis O MeOH O HO MeO O N N H N Hof(f)man(n) #1 (not much known on this one) 2 O Me O (K. A.) Hofmann-Sand Reaction (not the Hofmann with all the other reactions) (+)-cepharamine Oxymercuration of double bonds Hofmann Elimination (Annalen der Chemie und Pharmacie 1851, 78, 253) O OAc O O H H H Br R2 R2 R2 Hg Br2 1 MeI 1 Ag2O 1 + Hg(OAc) OMe OMe R R R R2 OMe 2 I 1 CH OH OH -H O R 3 N R3 N R4 H2O 3 N 4 2 MeO MeO R3 R4 R R Me Heat Me Berichte der deutschen chemischen Gesellschaft 1900, 33, 1340 - 1353 alkene formed often does not follow Zaitsev's rule 1 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008 Recent Example of Hofmann Elimination (Tetrahedron Lett. 1989, 30, 5989) Hofmann-Martius Reaction (Ber. 1871, 4, 742) OMe R NH NH NH 1) CH I O 2 2 MeO 3 MeO O - Similar to Fries Rearrangement 2) 20% NaOH R EtOAc steps HO + - R-group must be able an efficient cation stabilizer 85% H O O O O H R NMe2 (+)-picrasin Recent Example of Hofmann-Martius Reaction (Org. Lett. 2006, 8, 3497) Me Ph Ph Me Hofmann-Löffler-Freytag Reaction (Ber. 1883, 16, 558) Me PhMe/80 oC Cl N 2 NH or CF CO H NH N 3 2 (cat) MeHN O N NaOH O PhH/25 oC H (aq) ligroin Cl 71 or 82% H2SO4(aq) Creation of the Textile Dyeing Industry N N - Hofmann had his student Cl H HO (Perkin) attempt to oxidize N aniline to quinine Recent Example of Hofmann-Loffler-Freytag (Chem. Pharm. Bull. 1985, 33, 3187) MeO - led to black tar that made a bright purple solution in ethanol 1) Hg-lamp N NCS, DCM quinine CF3CO2H - purple solution was used to 0 oC 5h, r.t. N H N Cl N William Henry Perkin dye silk, Perkin became rich 2) 5% KOH, EtOH H C CH reflux, 2h, 39% Synthesis of first synthetic dye H3C CH3 3 3 Me Me N core of kobusine NH2 NH2 K2Cr2O7 H N N NH + 2 Hofmann Isocyanide Synthesis (aka carbylamine test) Me (impurity) + CHCl3 + KOH N qualitative test NH heat 2 C mauveine A "smell of isocyanides described by Hofmann and Guatier as " highly specific, almost prior to mauveine, purple dye came from the fresh mucus secretion from tthe overpowering, horrible, and extremely distressing" hypobranchial gland of a medium sized predatory sea snail (extremely expensive!!!) 2 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008 Hof(f)man(n) #3 - Bayer Pharmaceutical Chemist Hof(f)man(n) #5 - of Woodward-Hoffmann Rule Fame - synthesized aspirin (1897) and heroin (1897) in forms that could be used medicinaly - professor at Cornell University AcO - interests lie in the application of theoretical and computational OAc methods to inorganic and organic systems CO H 2 O N - Awards include: 1981 Nobel Prize Priestly Medal ACS Organic and Inorganic Award H Arthur C. Cope Award aspirin AcO National Medal of Science heroin Felix Hoffmann - also has an interest in and writes poetry Roald Hoffmann Hof(f)man(n) #4 - Father of LSD (and psilocybin) - first to synthesize, ingest and study the psychodelic Hof(f)man(n) #6 - Professor Emeritus, New Mexico State effects of LSD (synthesis 1938, test 1943) - was a chemist at Sandos (now Novartis) α-oxidation and installation of a leaving group (Synthesis 1985, 760) - accidently absorbed some through fingertip, then rode bike home (purposely ingested 0.25 mg the next day, 1 O see results below) R OAc Ethyl Acetate R2 Methanol R1 + (Ar-SO2-O)2 R3 - recently passed away (april 29, 2008, age 102) R2 R3 81-95% Albert Hofmann OSO2Ar O O Ar = O2N HN HO P N NMe - O H O Also applied to enamines (J. Org. Chem. 1985, 50, 5148) and Robert V. Hoffman β-ketoesters (J. Org. Chem, 1990, 55 ,1267) psilocybin LSD N H N H C-to-N Rearrangement of N-(Arylsulfonoxy)amine (J. Org. Chem. 1988, 53, 3317) First Accidental Experience With LSD - "In a dreamlike state, with eyes closed, I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours, this condition faded away." NH2 filter through warm o N (Ar-SO2-O)2 SiO2 (-78 C) to rt Second (0.25 mg experience), excerpts - commenting on his neighbour " She was no 82% longer Mrs. R. but rather a malevolent, insidious witch with a colored mask." EtOAc -78 oC "A demon had invaded me, had taken possesion of my body, mind and soul. I jumped Yields typically not this high, generally 40-80% up and screamed, trying to free myself of him, but sank down again and lay helpless on the sofa." 3 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008 Synthesis of α-azidoketones (J. Org. Chem. 1994, 59, 2902) Synthesis of 2-Oxazolone-4-carboxylates (J. Org. Chem. 2002, 67, 1102) O O - installation of halogen can be difficult O X - N O R1 N3 1 3 O R R OEt p-TsOH 2 - doesn't work well when β-hydrogens R (X = Cl, Br) R2 + O N MeO NH2 X O Toluene Solution Reflux X = ONs (AgOTf for X = Br) R CO2Et X = Br O O - -ONs can be installed regiospecifically ONs 1 N - N3 - reaction conditions milder than halide (rt) The Products can be hydrolyzed (ester), acylated (nitrogen), reduced (ester) R 3 R1 2 - yields range from 68-96% R R2 Generation and Trapping of α-Lactams by Weak Nucleophiles Hof(f)man(n) #7 - Professor, University of Marburg, Germany (J. Org. Chem. 2000, 65, 2591) General Reaction Main Research Focuses O O O O R 1) Total Synthesis of Natural Products Base R Nu: N Nu EtO2C R EtO 2) Chiral Organometallic Reagents EtO N N OMs O 3) Stereoselective allylboration reactions If a primary amine and excess base is used. Reinhard W. Hoffmann O O O NaH (1.2 eq) C6H11 N Example of Research Focus 1 and 3 (J. Am. Chem. Soc. 1997, 119, 7499) C6H11 NBn 65% EtO N BnNH2 THF, rt, 10h Previous work by others (for references see original paper) OMs O Br H H Sonication no nucleophile added H O Lewis Acid HO HO O or Protic Acid O O O + OAc NaH CH O O O CH3 O N 3 83% H EtO N H sonication M OMs EtO M = TMS BF3 Et2O Major M = trialkyltin BF3 Et2O Major Preparation of phosphonomethyl ureas M = tributyltin triflic acid Major O O O CH3 (+)-Laurencin Yields are low and the example to form the cis has never NaH P CH3 P N N been exploited further EtO N + EtO OEt N THF OEt 79% OMs H O 4 Baran Group Meeting I.S. Young So Many Hof(f)man(n)s 5/10/2008 Laurencin Continued - Use of Masking Strategy Interesting transformations along the way to the tetrahydropyran O iBu2Al OH MeO O HO N MeO O MeO OTBS Me N B OiPr 2. s-BuLi 3. O 1. DIBAL O OMe OBn H H Me OBn OH O -78 oC -78 oC KH, THF, 0 oC O Yb(OTf) Li 55 % Cl CCHCl, -78 -> 20 oC 3 2 79% MeCN O MeLi, -78 -> -40 oC 2. aq pH 7 2% H2O MeO rt N O HO 1) pinacolborane O B O 35% Me O Cp2ZrClH O O O + MeO Li O O B O 2) CH2ICl, n-BuLi B o OBn OTBS O O OMe OBn OTBS -100 -> 20 C 67% MeO OMe OMe What happens when the additional stereocenter is included? Research Area #2 - Chiral Grignard Chemistry O 1. DIBAL 2. s-BuLi So What is the Deal with the Chrial Grignard Reagents? MeO 3. HO HO O H N B OMe 2 Pd / C Debate about mechanism of Grignard Addition Me O - ionic could lead to enantioenriched products O 97% O 4.